This proposal will test the hypothesis that a specific native sequence of insulin including the dominant insulin peptide, amino acids B9 to B23, is essential for disease development for the NOD mouse. Within islets of NOD mice, T cells reacting with insulin comprise up to 50 percent of islet-specific T lymphocytes and are present as early as four weeks of age. The majority of these insulin reactive T cells (more than 90 percent) recognize an immunodominant T cell epitope of a peptide termed B2 or B:9-23 (amino acids 9 to 23 of the insulin B chain). Recently, it has been shown that the majority of T cells reacting with peptide B:9-23 express a shared T cell receptor alpha chain motif with utilization of a recently discovered V-alpha13 variant, V- alpha13.3a, and additionally express J-alpha 34 or 45, with the shared J- alpha motif KLTFGKGT. Similar restriction is not apparent in the T cell receptor beta chains of these clones.